Novel sustained release polymer

ABSTRACT

A polymer and a method for its preparation are provided. The polymer comprises poly(lactide), poly(lactide/glycolide) or poly(lactic acid/glycolic acid) segments bonded by ester linkages to both ends of an alkanediol core unit. The polymer is for use in a controlled release formulation for a medicament, preferably leuprolide acetate. The controlled release formulation is administered to a patient as a subcutaneous depot of a flowable composition comprising the polymer, a biocompatible solvent, and the medicament. Controlled release formulations comprising the polymer release leuprolide for treatment of prostate cancer patients over periods of 3-6 months.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of U.S. Ser. No. 10/872,671,filed Jun. 21, 2004, publication number US 2004/0229912, which is acontinuation of U.S. patent application Ser. No. 10/373,400, filed Feb.24, 2003 and issued as U.S. Pat. No. 6,773,714, which is a continuationof U.S. application Ser. No. 09/711,758, filed Nov. 13, 2000 and issuedas U.S. Pat. No. 6,565,874. All these applications are incorporated byreference herein in their entirety.

FIELD OF THE INVENTION

The field of the invention is a novel polymer composition for use in asustained release formulation for a medicament, the formulationcomprising the composition being emplaced within the tissue of a patientsuffering from a malcondition such as prostate cancer.

BACKGROUND OF THE INVENTION

Flowable, polymer-containing compositions useful as biodegradablecontrolled release formulations for medicinal substances are described,for instance, in U.S. Pat. Nos. 4,938,763; 5,702,716; 5,744,153;5,990,194; 5,324,519; 6,143,314; 6,630,155; 6,565,874; and 6,773,714.One type of controlled release formulation composition includes abiodegradable, water-insoluble polymer or copolymer and medicamentdissolved or dispersed in a bio-compatible organic solvent. Thesecompositions are administered in a flowable, preferably liquid state tothe patient, typically via a syringe needle. Once in the body, thepolymer of the composition coagulates into a semi-solid mass as at leastsome of the water-soluble organic solvent diffuses into surroundingtissues. This semi-solid mass of polymer and residual solvent serves tocontrol the release of the medicament as it diffuses out of the polymermass into surrounding tissues at a fairly constant rate.

This type of controlled release formulation has been found to beparticularly useful for treatment of prostate cancer. It is well-knownthat reduction of serum testosterone levels can inhibit the growth ofprostate cancer, and physical castration of prostate cancer patients,while an effective treatment, suffers from unpopularity among thepatients. However, certain medicinal compounds have been found toeffectively reduce serum testosterone levels without physical castration(orchiectomy) and have thus found use in prolonging the survival ofpatients afflicted with prostate cancer. One such compound isleuprolide, a synthetic peptide analog that is a “super-agonist” forleutinizing hormone receptors.

Various polymer compositions have been used for leuprolide controlledrelease formulations, and one group of polymers that have been found tobe well-suited for this use are the polyesters of lactic acid andglycolic acid. Copolymers comprising these monomers have been found topossess desirable attributes including low toxicity, non-allergenicity,and biodegradability in living tissue. These copolymers, includingpoly(lactide/glycolide) and poly(lactic acid-glycolic acid), may beproduced by a variety of methods and have a range of properties. Forexample, see: “One- and Three-Month Release Injectable Microspheres ofthe LH-RH Superagonist Leuprorelin Acetate,” H. Okada (1997), AdvancedDrug Delivery Reviews (Elsevier), 28, 43-70; “Biodegradable Polymers forSustained Drug Delivery,” A. Schindler, R. Jeffcoat, G. L. Kimmel, C. G.Pitt, M. E. Wall, and R. Zweidinger (1977), Contemporary Topics inPolymer Science, v. 2, 251-286, (Plenum Publishing Corp.).

There are a number of patents that discuss methods of preparation ofsuch polymers. One synthetic approach to polymers of this type involvesthe use of an initiator, a distinct compound that at the initial stagesof the polymerization reacts with monomeric units. As an initiator isincorporated into the polymer, it is distinct from a catalyst, whichaccelerates the polymerization reaction but is not incorporated into theproduct. The publication by Beck et. al. in Biology of Reproduction, 28,186-195 (1983) describes the use of lauryl alcohol as an initiator toproduce lactide/glycolide copolymers with known molecular weights. U.S.Pat. No. 4,137,921 (Okuzumi et al.) discusses the formation of PLGpolymers involving the use of a diethyleneglycol initiator oflactide/glycolide polymerization with stannous octanoate as a catalyst.U.S. Pat. No. 3,284,417 (Hostettler et al.) discusses the use of diolinitiators for polymerizations of lactones, wherein the lactones havingat least 6-8 carbon atoms. U.S. Pat. No. 4,767,628 (Hutchinson)discusses the preparation of lactide-glycolide copolymers using a lacticacid initiator with a stannous octanoate catalyst. Initiators are notalways used in the synthesis of polymers of this type. U.S. Pat. No.3,839,297 (Wasserman et al.) discusses the production oflactide/glycolide copolymers using stannous octanoate catalyst, but withno initiators.

There is an ongoing need for polymers that confer desirable controlledrelease properties on formulations adapted for the controlled release ofmedicaments in human patients for treatment of diseases such as prostatecancer.

SUMMARY OF THE INVENTION

The present invention provides a novel biodegradable polymer,specifically a biodegradable thermoplastic polyester, for use in arelatively long-lasting controlled release formulation adapted toprovide for the controlled release of a medicament in vivo. Thecontrolled release formulation comprising the biodegradable polymer ofthe present invention preferably also comprises leuprolide acetate fortreatment of human patients afflicted with prostate cancer.

The biodegradable polymer of the present invention is a composition ofmatter wherein two polylactide polymer segments (“PL polymer segments”)or two poly(lactide/glycolide) copolymer segments (“PLG copolymersegments”) or two poly(lactic acid/glycolic acid) copolymer segments(“PLGA copolymer segments”) or two poly(lactic acid) polymer segments(“PLA polymer segments”) are respectively covalently bonded at one end,bearing a carboxyl group, of each segment to the two hydroxyl groups ofa non-polymeric alkanediol core. Bonding is by an ester linkage betweenthe carboxy terminus of each of the copolymer segments and one of thetwo hydroxyl groups of the alkanediol respectively. The structure of thepolymer of the present invention can thus be expressed as: HO-(PLpolymer segment)-C(O)O-alkane-OC(O)-(PL polymer segment)-OH or HO-(PLGcopolymer segment)-C(O)O-alkane-OC(O)-(PLG copolymer segment)-OH orHO-(PLGA copolymer segment)-C(O)O-alkane-OC(O)-(PLGA copolymersegment)-OH or HO-(PLA polymer segment-C(O)O-alkane-OC(O)-(PLA polymersegment)-OH.

The copolymer segments for PLG and PLGA differ owing to the differingstarting materials used in their preparation and the manner in whichthey are incorporated into the growing polymer chain during thepolymerization reaction. The PLG segments include substantially onlyrepeating dimer units (-L-L-G-G-L-L-L-L-) wherein L-L represents aring-opened lactide dimer unit (lactide being the dimeric cyclic esterof lactic acid) and G-G represents a ring-opened glycolide dimer unit(glycolide being the dimeric cyclic ester of glycolic acid), while thePLGA segments include repeating monomer units (-L-G-L-G-L-) wherein Grepresents a glycolate (glycolic acid) unit and L represents a lactate(lactic acid) unit. The order or distribution of differing units withineach PLG or PLGA segment is substantially random, although therelatively higher rate of reaction of G or G-G over L or L-L will placea higher degree of G or G-G close to the alkanediol core for the PLGA orPLG copolymer segments respectively.

The polymerization reaction for a PLG copolymer segment, wherein G-G orL-L units are incorporated into the growing polymer chain, is aring-opening polymerization of the cyclic dimeric esters with a hydroxylgroup of an alkanediol molecule. A hydroxyl group of the alkanediolfirst reacts with either the G-G or L-L cyclic dimer to form an esterbond between the G-G or L-L open dimer carboxyl group and one of thealkanediol hydroxyl groups. Thus, the open dimer is bonded to thealkanediol at the carboxyl end of the initial unit of what will becomethe PLG (or PL) copolymer segment, the product having a free hydroxylgroup at the other end. This free hydroxyl group then reacts withanother G-G or L-L dimer to add another unit to the growing polymerchain. The same process takes place with the second hydroxyl group ofthe alkanediol core. When the polymerization reaction ceases, the finalproduct is a polymer that has terminal hydroxyl groups but substantiallyno terminal carboxyl groups, the carboxyl ends of the two copolymersegments being ester-linked to each of the two hydroxyl groups of thealkanediol core. The polymer thus contains substantially no titratablecarboxyl groups, and is a neutral not an acidic polymer. A preferredalkanediol initiator is a linear alkane α,ω-diol. A specific example is1,6-hexanediol.

The polymerization reaction used in the art for preparing PLGA or PLApolymers lacking a core unit is a condensation reaction where thecarboxyl group on either a G or L molecule (L only for PLA) reacts witha hydroxyl group on another G or L molecule to form a dimeric open esterwith the elimination of water. This linear dimer with a carboxyl groupat one end and a hydroxyl group at the other end then reacts with otherG or L molecules to form additional ester groups in the growing polymerchain. At the end of this condensation polymerization, the polymerchains all have a carboxyl group at one end of the polymer chain and ahydroxyl group at the other end of the polymer chain. Thus the artpolymer made in this manner is an acidic polymer.

However, when an alkanediol core is added at the beginning of thepolymerization according to a method of the invention, one of the twoalkanediol hydroxyl groups will react with a carboxyl group of either aG or L to form an alkanediol monoester with the carboxyl group of the Gor L, the hydroxyl group of the G or L again reacting with a G or L andso on, to form one of the two copolymer segments; the same process takesplace with the second alkanediol hydroxyl group yielding the secondcopolymer segment, the entire process finally providing a polymer withonly hydroxyl groups at both ends of the molecular chain. The resultantpolymer is neutral and not acidic. A preferred alkanediol initiator orcoupling agent is a linear α,ω-diol. A specific example is1,6-hexanediol.

It has unexpectedly been found that a polymer of the present invention,when incorporated into a controlled release formulation for leuprolidethat is emplaced within the tissues of a prostate cancer patient,provides for a surprisingly long-lasting time course of drug releasefrom the formulation. The time period over which sufficient leuprolideis released to maintain chemical castration levels of serum testosterone(0.5 ng/mL) is as long as 120 days or as long as 180 days. This propertyis highly advantageous from the medical perspective compared to ashorter time period for art polymers, such as 30 days, as it reduces thenumber of medical procedures a patient must endure in a course oftreatment, enhancing patient comfort and convenience and reducing cost.

A polymer of the present invention has a weight average molecular weightof about 6 kD to about 200 kD, preferably about 8 kD to about 100 kD,more preferably from about 15 kD to about 45 kD. The composition of eachPLG copolymer segment preferably comprises from about a 45/55 weightratio to about a 99/1 weight ratio of DL-lactide to glycolide. Thecomposition of each PLGA copolymer segment preferably comprises fromabout a 45/55 weight ratio to about a 99/1 weight ratio of DL-lactate toglycolate. Alternatively, a polymer of the present invention has thesame molecular weight ranges, but comprises PL or PLA polymer segments,wherein lactide (or equivalently, lactate) comprises 100% of the polymersegment.

The present invention further provides methods for the preparation ofthe polymers. A method according to the present invention comprisescontacting an alkanediol with lactide or with a mixture of lactide andglycolide in the presence of a suitable polymerization catalyst suchthat the alkanediol serves as an initiation site for the polymerizationof the lactide and glycolide units thereon. Thus, in a polymer formed bya method of the invention, the alkanediol becomes a core of a polymerwith PL or PLG copolymer segments covalently linked to the alkanediolcore and substantially only free hydroxyl group terminal ends. Anothermethod according to the present invention comprises contacting analkanediol with lactate or a mixture of lactate and glycolate in thepresence of a suitable condensation polymerization catalyst such thatthe alkanediol serves as an initiator or coupling agent for theformation of longer chain PLA or PLGA polymers, again with only hydroxylterminal ends. Thus, in a polymer formed by a method of the invention,the alkanediol becomes a core of a polymer with PLA or PLGA copolymersegments covalently linked to the alkanediol core.

A preferred method of preparation of a polymer of the invention includescontacting the reactants lactide, glycolide and the alkanediol in thepresence of a catalyst comprising a tin salt, preferably the tin salt ofan organic acid. A specific example of a catalyst is stannous octanoate.

A preferred method of the present invention further comprises contactingthe reactants lactide, glycolide and the alkanediol, and thepolymerization catalyst, at an elevated temperature. A preferredtemperature is about 140° C. The polymerization reaction can be carriedout without a solvent, as a neat melt. Further, the polymerizationreaction can be carried out in the absence of oxygen, such as under avacuum or under an inert atmosphere, for example nitrogen.

It has been surprisingly found that a controlled release formulationcomprising a polymer according to the present invention is capable ofsupporting sustained release of a medicament, for example leuprolide,over a relatively long time period. For example, it has beensurprisingly found that a controlled release formulation including apolymer according to the present invention when emplaced in a tissue ofa patient in need thereof is capable of providing for sustained releaseof leuprolide for a period of about 90 days, or about 120 days, or about180 days.

The controlled release formulation according to the present inventioncomprises a polymer of the invention, a medicament such as leuprolide,and an organic solvent. The organic solvent dissolves the polymer andthe medicament. Preferably the organic solvent is water-soluble at leastto some degree, such that when a flowable composition comprising thecontrolled release formulation is emplaced within a tissue of a patientin need thereof, the polymer coagulates from solution as the organicsolvent diffuses away into the surrounding aqueous body fluids. Thiscoagulated composition then slowly releases the medicament over a periodof time. A type of organic solvent that can be used comprises amides.Specific examples are N-methylpyrrolidone, N,N-dimethylformamide, andN,N-dimethylacetamide.

The polymer of the present invention can be present in any suitableamount in the flowable composition comprising the controlled releaseformulation. The polyester is preferably present in about 30 wt. % toabout 70 wt. % of the flowable composition and more preferably ispresent in about 35 wt. % to about 60 wt. % of the flowable composition.

DETAILED DESCRIPTION OF THE INVENTION

Reference will now be made in detail to certain features of theinvention, examples of which are illustrated in the accompanyingstructures and formulas. While examples of the invention will bedescribed in conjunction with the enumerated claims, it will beunderstood that it is not intended to limit the claimed invention tothose examples. On the contrary, the invention is intended to cover allalternatives, modifications, and equivalents which may be includedwithin the scope of the present invention as defined by the claims.

References in the specification to “one embodiment”, “an embodiment”, “apreferred embodiment”, etc., indicate that the embodiment described mayinclude a particular feature, structure, or characteristic, but everyembodiment may not necessarily include the particular feature,structure, or characteristic. Moreover, such phrases are not necessarilyreferring to the same embodiment. Further, when a particular feature,structure, or characteristic is described in connection with anembodiment, it is submitted that it is within the knowledge of oneskilled in the art to affect such feature, structure, or characteristicin connection with other embodiments whether or not explicitlydescribed.

DEFINITIONS

A “polymer” as used herein refers to a macromolecular organic compoundthat is largely, but not necessarily exclusively, formed of repeatingunits covalently bonded in a chain, which may be linear or branched. A“repeating unit” is a structural moiety of the macromolecule which isfound more than once within the macromolecular structure. Typically, apolymer is composed of a large number of only a few types of repeatingunits that are joined together by covalent chemical bonds to form alinear backbone, from which substituents may or may not depend in abranching manner. The repeating units can be identical to each other butare not necessarily so. Therefore a structure of the type -A-A-A-A-wherein A is a repeating unit is a polymer, also known as a homopolymer,and a structure of the type -A-B-A-B- or -A-A-A-B-A-A-A-B- wherein A andB are repeating units, is also a polymer, and is sometimes termed acopolymer. A structure of the type -A-A-A-C-A-A-A- or -A-B-A-C-A-B-A-wherein A and B are repeating units but C is not a repeating unit (i.e.,C is only found once within the macromolecular structure) is also apolymer under the definition herein. When C is flanked on both sides byrepeating units, C is referred to as a “core” or a “core unit.” A shortpolymer, formed of up to about 10 repeating units, is referred to as an“oligomer.” There is theoretically no upper limit to the number ofrepeating units in a polymer, but practically speaking the upper limitfor the number of repeating units in a single polymer molecule may beapproximately one million. However, in the polymers of the presentinvention the number of repeating units is typically in the hundreds.

A “copolymer” is a variety of polymer wherein non-identical repeatingunits are present. A copolymer may be regular or random in the sequencedefined by the more than one type of repeating unit. Some types ofcopolymers are random copolymers, graft copolymers and block copolymers.

A “polymer segment” or a “copolymer segment” as used herein refers to aportion or moiety of a larger molecule wherein that segment is a sectionof a polymer or a copolymer respectively that is bonded to otherportions or moieties to make up the larger molecule. When the polymersegment or a copolymer segment is attached to the larger molecule atonly one end of the segment, the end of attachment is the “proximal end”and the other, free end is the “distal end.”

A “core” or a “core unit” as used herein refers to a portion or moietyof a polymer that is not itself a copolymer segment, but is incorporatedwithin the polymer chain and has at least one polymer or copolymersegment bonded to it. A core may have two or more polymer or copolymersegments bonded to it. A core may be formed from a molecule that isincorporated into the polymer chain that grows from it during thepolymerization reaction.

The term “lactide” as used herein, when referring to the chemicalcompound itself, for example as the “lactide reagent” or “lactidereactant” means the dimer cyclic ester of lactic acid:

The lactide may be of any configuration at the chiral carbon atoms(bearing the methyl groups) within the meaning of the term herein. Itmay also be a mixture of molecules with different configurations at thechiral carbon atoms. Thus, lactide may be DD-, DL-, LD-, LL-lactide, orany mixture or combination thereof.

When referring to a polymer such as a poly-lactide or apoly(lactide-glycolide) containing a “lactide” unit, the term “lactide”or “lactide unit” means the ring-opened species consisting of two lacticacid units joined by an ester bond which can be further incorporatedinto a polymeric chain with other such units or with other types ofrepeating units. One end of the lactide unit comprises a carboxyl groupthat may be bonded to an adjacent atom via an ester linkage, or an amidelinkage, or via any other type of bond that a carboxyl group may form.The other end of the lactide unit comprises a hydroxyl group that may bebonded to an adjacent atom via an ester linkage, an ether linkage, orvia any other type of bond that a hydroxyl group may form.

A “lactide” in a poly-lactide polymer thus refers to the repeating unitof the polymer that can be viewed structurally as being formed from apair of lactic acid molecules, with the understanding that the wavylines indicate points of attachment to neighboring groups:

Again, the configuration at the chiral carbon atoms includes any and allpossible configurations and mixtures thereof, as described above for thecyclic dimer.

Similarly, the term “glycolide” as used herein, when referring to thechemical compound itself, such as the “glycolide reagent” or the“glycolide reactant” means the dimer cyclic ester of glycolic acid:

but when referring to a “glycolide” unit in a polymer, the term refersto the repeating unit, a dimer of glycolic acid as shown:

Similarly to the lactide unit, one end of the glycolide unit comprises acarboxyl group that may be bonded to an adjacent atom via an esterlinkage, or an amide linkage, or via any other type of bond that acarboxyl group may form, and the other end of the glycolide unitcomprises a hydroxyl group that may be bonded to an adjacent atom via anester linkage, an ether linkage, or via any other type of bond that ahydroxyl group may form.

It should be understood that those in the art comprehend that a“lactide” or a “glycolide” as used herein in either sense is itself adimer of lactic acid or glycolic acid respectively, either cyclic orlinear. In a polymer composed of such dimeric molecular species, therepeating unit as defined herein is therefore formally itself a dimer.Polymers of this type are referred to herein as “polylactide” or“poly(lactide-glycolide).”

It is well-known that there are other polymers known in the art as“poly-lactic acid” or “poly-glycolic acid” that are formed frompolymerization of the monomers, either lactate (lactic acid) orglycolate (glycolic acid). There are also copolymers known in the art as“poly(lactic acid-glycolic acid)” or “poly(lactate-glycolate).” Inpolymers of this type, the repeating unit is a monomer comprising lacticacid, glycolic acid, or both.

When a polymer is formed only of lactic units, or only of glycolicunits, the distinction is relatively insignificant except as regards themethod by which the polymer is made. However, when a polymer is formedof a mixture of lactic and glycolic units, the distinction isstructurally important. For example, a polymer formed of monomericlactate and glycolate units may comprise sequences of the type -L-G-L-G-where L is a lactate unit and G is a glycolate unit. However, in apolymer formed of lactide and glycolide units, such a sequence would notbe found unless rearrangement occurs, because the repeating units jointhe polymer as pairs of lactic and glycolic units. Thus, sequences suchas -L-L-G-G- or -L-L-L-L-G-G-would typify a polymer formed of thelactide and glycolide units, and could by chance also be found in apolymer formed of the monomeric lactate and glycolate units, but in apolymer formed of the dimeric units each type of repeating unit wouldsubstantially always comprise a pair of identical monomeric units, soone would not expect to find sequences of the -L-G-L-G- type. Due tothis potential ambiguity, it is important to differentiate these twotypes of polymers.

As used herein, the term “poly(lactide-glycolide)” or the term “PLG”refers solely to a copolymer or a copolymer segment formed of thedimeric repeating units, wherein the dimeric lactide and dimericglycolide units make up the polymeric chain. A poly(lactide-glycolide)is typically formed through polymerization of the cyclic dimers lactideand glycolide, although theoretically it could be formed through anyprocess wherein dimeric units are incorporated in a given step of thepolymerization process. The terms “polylactide” and “PL” refer to apolymer or a polymer segment wherein only lactide repeating units arepresent. They are formed from polymerization of lactide, and are thusanalogous to PLG polymers.

The terms “poly(lactic acid-glycolic acid),” “poly(lactate-glycolate),”or “PLGA” refer solely to a polymer formed of the monomeric repeatingunits, wherein monomeric lactate and glycolate units make up thepolymeric chain. A poly(lactic acid-glycolic acid) is formed bypolymerization of monomeric lactic acid and monomeric glycolic acid orderivatives of those acids such as lower alkyl esters. Analogously, theterms “polylactate” and “PLA” refer to polymer or polymer segmentswherein only lactate repeating units are present. They are formed bypolymerization of lactate.

A “titratable carboxylic acid group” as used herein refers to acarboxylic acid group in free form, that is, not bound as an ester orother derivative, wherein the carboxylic acid group can bear a freeproton which may dissociate (ionize) in aqueous solution to form acarboxylate anion and a proton (acid). Therefore, an organic polymerwith no titratable carboxylic acid groups is not an acidic polymer, andall carboxylate moieties within the polymer are bonded into esters,amides, or other non-acidic derivatives.

“Alkanediol” as used herein refers to a saturated, branched or straightchain or cyclic alkane diradical of about 4 to about 8 carbon atoms,having two monovalent radical centers derived by the removal of twohydrogen atoms from different carbon atoms of the parent alkane, whereineach monovalent radical center bears a hydroxyl group. Thus, analkanediol is a dihydroxyalkane. Alkane diradicals include, but are notlimited to: 1,4-butylene(-CH₂CH₂CH₂CH₂—), 2,3-butylene(CH₃ĊHĊHCH₃),1,6-hexylene(-CH₂CH₂CH₂CH₂CH₂CH₂—),1,4-cyclohexanedimethyl(-CH₂-cyclohexyl-CH₂—), and the like. Typicalalkanediols of the invention therefore include, but are not limited to,1,4-butanediol(HOCH₂CH₂CH₂CH₂OH), 2,3-butanediol(CH₃CH(OH)CH(OH)CH₃),1,6-hexanediol(HOCH₂CH₂CH₂CH₂CH₂CH₂OH), cyclohexane-1,4-dimethanol, andthe like. An alkanediol may be optionally substituted with otherfunctional groups on the carbon atoms that form the alkane moiety,including but not limited to groups such as alkoxy, hydroxy, halo,cyano, carboxy, alkylcarboxy, carboxamido, alkyl or dialkyl carboxamido,alkyl or aryl thio, amino, alkyl or dialkyl amino, aryl, or heteroaryl.

An “α,ω-diol” refers to an alkanediol wherein the two hydroxyl groupsare disposed respectively on the two terminal carbon atoms of an alkanechain. Typical α,ω-diols are 1,4-butanediol and 1,6-hexanediol. Anα,ω-diol comprises two primary hydroxyl groups.

As used herein, the term “inherent viscosity” refers to the standardpolymer parameter defined as the natural logarithm of the relativeviscosity of a polymer solution divided by the concentration of thepolymer in the solution. The relative viscosity is the ratio of theviscosity of the polymer solution to the viscosity of the solvent alone.

A “number average molecular weight” refers to the standard polymerparameter defined as the total weight of a sample divided by the totalnumber of polymer molecules in the sample:

${\overset{\_}{M}}_{n} = \frac{\Sigma_{i}\mspace{14mu} N_{i}M_{i}}{\Sigma_{i}\mspace{14mu} N_{i}}$

A “weight average molecular weight” refers to the standard polymerparameter defined as:

${\overset{\_}{M}}_{w} = \frac{\Sigma_{i}\mspace{14mu} N_{i}M_{i}^{2}}{\Sigma_{i}\mspace{14mu} N_{i}M_{i}}$

where N_(i) is the number of molecules of molecular weight M_(i).

The “polydispersity” or “polydispersity index” is the ratio of theweight average molecular weight to the number average molecular weightof a polymer sample, and is a measure of the narrowness or broadness ofthe distribution of all the individual molecular weights of each polymermolecule in the sample.

DESCRIPTION OF THE INVENTION

The present invention provides a biodegradable polymer for use in acontrolled release formulation with a relatively long-lived duration ofeffectiveness, that is, with a relatively long time period over which amedicament is released from the polymer in therapeutically effectivequantities. A flowable composition comprising the novel polymer for useas a controlled release formulation further includes a solvent and amedicament, as is described in U.S. Pat. No. 6,773,714 and documentscited therein, which are incorporated herein by reference. The flowablecomposition may be used to provide a biodegradable or bioerodiblemicroporous implant formed in situ in animals.

A polymer of the present invention comprises two poly(lactide-glycolide)copolymer segments, or two poly(lactate-glycolate) copolymer segments,or two polylactide polymer segments, or two polylactate polymersegments, respectively covalently bonded to the two hydroxyl groups ofan alkanediol core unit. In contrast to many polymers known in the art,the polymers of the invention do not comprise titratable carboxylic acidgroups, being hydroxyl-terminated at the distal ends of both PLG or PLGAcopolymer segments or PL or PLA polymer segments. This is due to thefact that the carboxyl ends of the copolymer segments are bonded inester linkages with the hydroxyl groups of the alkanediol core. Theabsence of titratable carboxylic acid groups in the polymer of theinvention means that the chemical functionality present on the terminalends of the polymer, that is, on the groups at the distal ends of thecopolymer segments linked to the alkanediol, are chemically neutral. Bychemically neutral it is meant that the groups are not acidic oralkaline, and are not ionizable in aqueous solution at around neutralpH. The chemical neutrality of the polymer is an outstanding advantageof the invention in that no acidic groups are present in the polymer tobring about auto-catalytic degradation through hydrolysis of the esterbonds of the polymer, or to catalyze degradation of a containedmedicament, such as the peptide analog leuprolide, or to react with thecontained medicament, such as with the amine groups on the peptideanalog leuprolide.

A polymer of the present invention can be represented structurally as acompound of Formula (I):

wherein “L/G” signifies a PLG copolymer segment, the H atoms at bothdistal ends signify the hydrogen atoms borne by the terminal hydroxylgroups, and R^(a) is an alkylene diradical. The R^(b) and R^(c) groupsshown on either side of the R^(a) core moiety may be either hydrogen ormethyl, with the proviso that both R^(b) groups are either hydrogen ormethyl concurrently, and both R^(c) groups are either hydrogen or methylconcurrently, but R^(b) and R^(c) need not be the same.

The groups indicated as “L/G” in Formula (I) thus signifylactide/glycolide copolymer segments of the structure:

wherein the R^(d) groups are independently hydrogen or methyl, againwith the proviso that as described above, hydrogen substituents ormethyl substituents are found in pairs due to their incorporation inpairs as repeating units from the dimeric lactide or glycolide reagents.Other than this requirement of R^(d) groups being in pairs, methylgroups and hydrogen groups are arranged randomly throughout thecopolymer segments L/G, with the understanding that due to the higherrate of reaction of G-G groups, these will tend to be more frequentlyfound adjacent to R^(a). The wavy lines signify points of attachment toother radicals, for example hydrogen atoms at the distal ends and thecore alkanediol hydroxyl groups at the proximal ends. The number ofrepeating units n range from about 20 up to about 750 for each copolymersegment, providing a polymer of a molecular weight of about 6 kD rangingup to about 200 kD in weight. It is understood that the two L/Gcopolymer segments need not be identical, and likely are not identical,either in sequence or in the molecular weight of each copolymer segmentin a given polymer molecule. Further, the specific composition of eachmolecule within a sample of the polymer varies in the same manner.

Another polymer of the present invention can be represented structurallyas a compound of Formula (II):

wherein “Lt/Gt” signifies a PLGA copolymer segment, the H atoms at bothdistal ends signify the hydrogen atoms borne by the terminal hydroxylgroups, and R^(a) is an alkylene diradical. The R^(b) and R^(c) groupsshown on either side of the R^(a) core moiety may be either hydrogen ormethyl. There is no restriction that the methyl groups or the hydrogenatoms occur in pairs.

The groups indicated as “Lt/Gt” in Formula (II) thus signifylactate/glycolate copolymer segments of the structure:

wherein the R^(d) groups are independently hydrogen or methyl. Methylgroups and hydrogen groups are arranged randomly throughout thecopolymer segments L/G, with the understanding that due to the possiblyhigher rate of reaction of G groups, these may tend to be morefrequently found adjacent to R^(a). The wavy lines signify points ofattachment to other radicals, for example hydrogen atoms at the distalends and the core alkanediol hydroxyl groups at the proximal ends. Thenumber of repeating units n may range from about 20 up to about 185 foreach copolymer segment, providing a polymer of a molecular weight ofabout 6 kD ranging up to about 50 kD in weight. It is understood thatthe two PLGA copolymer segments need not be identical, and likely arenot identical, either in sequence or in the molecular weight of eachcopolymer segment in a given polymer molecule. Further, the specificcomposition of each molecule within a sample of the polymer varies inthe same manner.

Yet another polymer of the present invention can be representedstructurally as a compound of Formula (III):

wherein L signifies a polylactide or polylactate polymer segment, the Hatoms at both distal ends signify the hydrogen atoms borne by thehydroxyl groups, and R^(a) is an alkylene diradical. The R^(b) groups oneither side of the R^(a) core moiety are all methyl.

As is described above, in the polymers of formulas (I), (II), and (III),the distal ends of the copolymer segments comprise hydroxyl groups. Theproximal ends of the copolymer segments therefore comprise the carboxylmoieties at the opposite end of the lactide or the glycolide repeatingunit, which are linked in ester bonds with hydroxyl groups of the corealkanediols. This structural element is an outstanding feature of thepresent invention, as it results in the lack of titratable carboxylicacid groups in a polymer of the invention, the product being a neutralpolymer.

The core alkanediol can be an α,ω-diol to which the copolymer segmentsare bonded via the two primary hydroxyl groups. Specific examples ofα,ω-diols include 1,4-butanediol, 1,5-pentanediol, 1,6-hexanediol,1,7-heptanediol and 1,8-octanediol. A particularly preferred alkanediolis 1,6-hexanediol.

The polymer of Formula (I) may be formed by a polymerization reactionwherein the core alkanediol comprising R^(a) serves as a site forinitiation of ring-opening polymerization of the lactide and glycolidereagents. The molar percent, and thus the weight percentage, of thealkanediol that is present in the polymerization reaction has aninfluence on the molecular weight of the biodegradable polymer that isformed. Use of a higher percentage of the alkanediol in thepolymerization reaction provides, on the average, a polymer of lowermolecular weight that has relatively shorter PL or PLG copolymersegments linked to the alkanediol core.

A preferred embodiment according to the present invention is a method ofpreparation of a polymer of Formula (I), comprising contacting analkanediol, glycolide, lactide, and a catalyst, the catalyst beingadapted to catalyze the ring-opening polymerization of the lactide andthe glycolide initiated on the alkanediol.

A polymer of the present invention comprising PLG copolymer segments ispreferably prepared using a catalyst suitable for ring-openingpolymerization of lactide and glycolide. The catalyzed ring openingreaction initially takes place between the lactide or glycolide reagentand a hydroxyl group of the alkanediol core unit such that the lactideor a glycolide unit forms an ester bond. Thus, after the first step ofpolymerization, only hydroxyl groups on the growing polymer chaincontinue to be available for further lactide or glycolide addition. Aspolymerization continues, each step continues to result in formationonly of hydroxyl-terminated copolymer segments attached to thealkanediol. In this manner, polymerization takes place until the supplyof lactide and glycolide reagents is exhausted, producing the hydroxylgroup terminated polymer. It is understood that a polymer of the presentinvention comprising PL copolymer segments can be made in the samemanner, only omitting the glycolide reagent.

The alkanediol can be an α,ω-diol such as 1,6-hexanediol. The alkanediolmay be present in the polymerization reaction mixture in amounts rangingfrom about 0.05% to about 5.0%, preferably from about 0.5% to about2.0%.

The catalyst may be any catalyst suitable for ring-openingpolymerization, but a preferred catalyst is a tin salt of an organicacid. The tin salt may be either in the stannous (divalent) or stannic(tetravalent) form. A particularly preferred catalyst is stannousoctanoate. The catalyst may be present in the polymerization reactionmixture in any suitable amount, typically ranging from about 0.01 to 1.0percent.

The polymerization reaction may be carried out under a variety ofconditions of temperature, time and solvent. Alternatively, solvent maybe absent and the polymerization be carried out in a neat melt. Thepolymerization reaction wherein the reactants comprise an alkanediol(such as hexane-1,6-diol), lactide, and glycolide in defined proportionsby weight, and a catalyst such as stannous octanoate, is preferablycarried out as a neat melt in the absence of oxygen at elevatedtemperature for a period of at least several hours. Preferably thereaction is carried out at about 140° C., either under vacuum or underan atmosphere of an inert gas such as nitrogen.

The weight percent, and thus mole percent, of lactide or glycoliderepeating units in the polymer can be varied by altering the weightpercentages of the two reactants present in the polymerization reactionmixture. The properties of the polymer can be changed by variations inthe ratio of the lactide to the glycolide monomer components, and by thepercent of the alkanediol initiator that is present.

Specifically, the molecular weight range of the polymer can becontrolled by the amount of core alkanediol present in thepolymerization reaction. The greater the weight percentage, and thus thegreater the mole fraction of the alkanediol in the polymerizationreaction mixture, the shorter are the chain lengths of the polymersattached to the alkanediol core due to the decreased availability oflactide or glycolide reagent molecules per initiating hydroxyl group.

The ratio of lactide to glycolide in the PLG copolymer segment is withina range of about 45/55 to about 99/1. Preferably, the ratio is within arange of about 70/30 to about 90/10. In a specific example, the ratio isabout 75/25. In another specific example the ratio is 85/15.

The weight average molecular weight of the polymer can be about 19 toabout 30 kD and the polydispersity index about 1.4 to about 1.8. In aspecific example, the weight average molecular weight is about 21 kD andthe polydispersity index is about 1.5. The inherent viscosity of thepolymer determined in chloroform can be about 0.23 to 0.31 dL/gm. In aspecific example the inherent viscosity is 0.25 dL/gm. In anotherspecific example the inherent viscosity is 0.27 dL/gm. In a method ofmanufacture according to the present invention, these variables may becontrolled by a person of skill in the art through controlling therelative starting weights of the lactide and the glycolide in thepolymerization reactor, the relative amount of the alkanediol initiator,and the identify and relative quantity of the catalyst used, among otherfactors.

Another method for preparing a polymer of the invention comprising PLGAcopolymer segments comprises contacting an alkanediol, glycolic acid,lactic acid, and a catalyst, the catalyst being adapted to catalyzecondensation of the lactate and the glycolate with the alkanediol.Again, the alkanediol can be a linear α,ω-diol. A specific example ishexane-1,6-diol. A typical catalyst for the condensation of lactate andglycolate units is an ion exchange resin, a metal oxide such as zincoxide or antimony oxide, or the reaction is self-catalyzed by lacticacid and/or glycolic acid.

Yet another method for preparing a polymer of the invention comprisingPLA copolymer segments comprises contacting an alkanediol, lactic acid,and a catalyst, the catalyst being adapted to catalyze condensation ofthe lactic acid with the alkanediol. Again, the alkanediol can be alinear α,ω-diol. A specific example is hexane-1,6-diol. A typicalcatalyst for the polymerization of lactic acid is an ion exchange resin,a metal oxide such as zinc oxide or antimony oxide, or the reaction isself-catalyzed by lactic acid.

A polymer of the present invention is substantially insoluble in waterand body fluid, biocompatible, and biodegradable and/or bioerodiblewithin the body of an animal. A flowable composition comprising apolymer of the invention, a medicament, and an organic solvent, isadministered as a liquid or flowable gel to tissue wherein thecontrolled release implant is formed in situ. The composition isbiocompatible and the polymer matrix does not cause substantial tissueirritation or necrosis at the implant site. The implanted compositioncan be used to deliver leuprolide acetate over a period of time, as isuseful for treatment of prostate cancer among other malconditions.

A flowable composition is provided in which a polymer of the inventionand a medicament, preferably leuprolide acetate, are dissolved in abiocompatible polar aprotic solvent to form the composition, which canthen be administered via a syringe and needle. After administration, theflowable composition coagulates in contact with body fluid to produce acontrolled release formulation of the medicament. The properties of thecontrolled release formulation will typically depend upon the molecularweight and amount of biodegradable thermoplastic polyester present. Forexample, the molecular weight of the polymer and the amount present inthe composition can influence the length of time over which theleuprolide acetate is released into the surrounding tissue. The polymercan be present in about 40 wt. % to about 50 wt. % of the composition;and can have an average molecular weight of about 15,000 to about30,000, as is disclosed in U.S. Pat. No. 6,773,714. The leuprolide canbe present in various quantities, but preferably is present in the rangeof about 3% to about 15% by weight.

Use of a polymer of the present invention in a controlled releaseformulation has surprisingly been found to provide for a relatively longduration of release of the medicament from the formulation. For example,using leuprolide acetate as the medicament, it has been unexpectedlyfound that sustained release of the leuprolide from an implantincorporating a polymer of the present invention persists as long asabout 90 days or about 120 days or about 180 days after implantation.Specifically, in preferred embodiments of the present invention, thecomposition can be used to formulate a three month, a four month, or asix month controlled release delivery system for leuprolide acetate foruse in a human patient afflicted with prostate cancer.

When the medicament that is formulated for controlled release isleuprolide acetate, as is used in the treatment of prostate cancer, theefficacy of the release can be monitored by following the serumtestosterone level in the patient being treated. The methods used indetermining the time period over which release of leuprolide issustained in such a course of treatment and the results of theexperiments in that regard are disclosed in “A Clinical Study of 22.5 mgLA-2550: A New Subcutaneous Depot Delivery System for Leuprolide Acetatefor the Treatment of Prostate Cancer,” Franklin M. Chu, Maury Jayson,Martin K. Dineen, Ramon Perez, Richard Harkaway, and Robert C. Tyler(2002), Journal of Urology, 168(3), 1199-1203, which is incorporatedherein by reference. It is disclosed therein that surprisingly, acontrolled release formulation of leuprolide acetate comprising apolymer of the present invention, injected subcutaneously to form adepot containing 22.5 mg of leuprolide acetate, is effective inmaintaining serum testosterone levels at less than “chemical castration”levels of 50 ng/mL for a period of about 3 months.

The greater duration of leuprolide release in a controlled releaseformulation of leuprolide acetate comprising a polymer of the presentinvention relative to controlled release formulations containing otherpolymers is described in “Sustained Suppression of Pituitary-GonadalAxis with an Injectable, In Situ Forming Implant of Leuprolide Acetate,”Harish B. Ravivarapu, Katie L. Moyer, and Richard L. Dunn (2000), J.Pharm Sci., 89(6), 732-741, which is incorporated herein by reference.In is disclosed therein that surprisingly, controlled releaseformulations comprising a polymer of the present invention suppressserum testosterone levels to chemical castration levels of less than 50ng/mL for periods in excess of 3 months, in contrast of controlledrelease formulations containing other polymers wherein serumtestosterone levels were controlled for only about half or less of thattime period. Among formulations comprising PLG type polymers(Formulations 2-6), Formulation 2, comprising polymers of the presentinvention including a hexanediol core, provided for sustained release ofleuprolide sufficient to keep blood testosterone levels at chemicalcastration levels for periods in excess of 100 days, whereasFormulations 4-6 comprising polymers lacking the hexanediol core onlysuppressed serum testosterone levels for a period of about 40-50 days.The polymers in Formulations 4-6 were those with carboxyl end groupswhich catalyzed the degradation of the polymer. As a result of theincreased degradation rate, these polymers did not remain in the bodyfor a sufficient time to provide the controlled release of leuprolideout to 90 days as needed. Formulation 1 also contained a polymer withcarboxyl end groups. This PLA polymer was similar to those used in theLupron Depot 90 and 120 day controlled release leuprolide products.Although this carboxyl end group polymer was able to last for 90 days,the initial release of leuprolide was not adequate to suppress thetestosterone levels below castrate levels as with the 1,6-hexanediolpolymer used in Formulation 2. The hydrophobic character of polylactateinhibits the initial hydration and release of the drug, and drug is onlyreleased at a sufficient rate after significant polymer degradation hasoccurred. In contrast, the terminal hydroxyl groups on the1,6-hexanediol polymer provides the hydrophilicity needed for thepolymer implant to quickly hydrate and release the leuprolide during theinitial phase of release, and then the polymer slowly degrades withoutthe catalytic action of terminal carboxyl groups. In this way, therelease of the drug is maintained for the desired 90 days.

The initial and prolonged period of release of leuprolide whenincorporated into the sustained release formulation of the invention,compared to the period of release of leuprolide when incorporated intoprior art formulations, was unexpected, but offers the prospect ofsustained release formulations that need to be administered to thepatient less often. This is evidenced by the surprisingly long durationof controlled release of leuprolide and the resulting suppression ofserum testosterone in the patient for a period in excess of 4 months ina controlled release formulation comprising a polymer of the presentinvention as disclosed in “An Eight-Month Clinical Study of LA-2575 30.0mg: A New 4-Month, Subcutaneous Delivery System for Leuprolide Acetatein the Treatment of Prostate Cancer,” Oliver Sartor, Martin K. Kineen,Ramon Perez-Marreno, Franklin M. Chu, Graham J. Carron, and Robert C.Tyler (2003), Urology, 62(2), 319-323, which is incorporated herein byreference. In a study of 90 human patients, a flowable composition(about 0.5 mL) of a controlled release formulation containing 30 mg ofleuprolide acetate was injected subcutaneously. Blood samples werecollected over a period of 112 days and analyzed for testosterone. Itwas observed that only 3.6% of the patients failed to maintain chemicalcastration levels of serum testosterone of less than 50 ng/mL over thistime period. Over 90% of the patients had their serum testosteronelevels reduced to below 20 ng/mL by this treatment regime.

A controlled release formulation for leuprolide comprising a polymer ofthe invention wherein a 6-month sustained release is achieved isdescribed in E. David Crawford, et al. (2006), “A 12-month clinicalstudy of LA-2585 (45.0 mg): A new 6-month subcutaneous delivery systemfor leuprolide acetate for the treatment of prostate cancer,” TheJournal of Urology, 175, 533-536. This publication, incorporated hereinby reference, discloses a formulation of leuprolide acetate comprising apolymer of the present invention in a flowable composition, wherein adepot administered approximately every 6 months (168 days) served tokeep serum testosterone at chemical castration levels over the period ofa year.

All publications, patents, and patent documents are incorporated byreference herein, as though individually incorporated by reference. Theinvention will now be illustrated with the following non-limitingexamples.

EXAMPLES Example 1 Preparation of Polymer General Procedure

In a jacketed stainless steel polymerization vessel, appropriate amountsof lactide and glycolide are added and the vessel contents are placedunder a nitrogen atmosphere. The temperature of the vessel is increaseduntil the reagents melt. An appropriate amount of an alkanediol is thenadded, followed by addition of stannous octanoate catalyst. The vesselis then heated at about 135-145° C. under nitrogen atmosphere for about3-4 hours with constant stirring. Then, to remove unreacted lactide andglycolide monomers, the vessel is evacuated and the monomers are vacuumdistilled out of the polymerization mixture. The hot melt is thenextruded into cooling pans. After cooling, the solid mass is cryo-groundto a fine powder and dried.

Example 2 Preparation of a Leuprolide Acetate Controlled ReleaseFormulation

A sample of a controlled release formulation for use as a subcutaneousdepot was prepared from a polymer prepared as described in Example 1,with a 75/25 lactide to glycolide weight ratio. The polymer andN-methylpyrrolidone were mixed in a 45/55 weight ration until thepolymer was completely dissolved in the solvent, then the polymersolution was further mixed with leuprolide acetate to provide aformulation wherein 0.375 gm (about 0.37 mL) of the flowable compositioncontained 22.5 mg of leuprolide acetate. The mixing was carried out byplacing the polymer solution in one syringe, the leuprolide acetate as alyophilized solid in a second syringe, connecting the two syringes witha luer-lock type connector, and exchanging the contents of the syringes.The solution, a flowable composition, was of sufficient liquidity to betransferred into a patient through a ⅝ inch 20 gauge syringe needle.

Example 3 Treatment of Prostate Cancer Patients with LeuprolideControlled Release Formulation Comprising Polymer of the PresentInvention

The solution of Example 2 was injected into the upper right or leftabdominal quadrants of 117 patients, 0.37 mL per patient, the patientsbeing afflicted with prostate cancer not previously treated to reduceserum testosterone levels. A depot volume of 0.37 mL was delivered ineach case to provide a total of 22.5 mg leuprolide acetate over theperiod of release. Blood samples were collected and analyzed fortestosterone and leutinizing hormone (LH). From a baseline level ofabout 400-600 ng/dL, testosterone levels dropped to below 20 ng/dL byabout day 20 and remained at that level until day 84, when a seconddepot was injected. Serum testosterone levels were observed to continueto be maintained at or below 20 ng/dL until the end of the study at 168days. Similarly, LH levels dropped from a pre-treatment baseline ofabout 10 mIU/mL to below 1 mIU/mL at about 20 days and maintained atthat level until the end of the study.

Example 4 Preparation and Treatment of Prostate Cancer Patients with aLeuprolide Acetate Controlled Release Formulation Comprising a Polymerof the Present Invention

A controlled release formulation, comprising 30 mg of leuprolide acetateper 0.5 mL of a flowable composition comprising a polymer of theinvention and N-methylpyrrolidone, prepared analogously to Example 2,was injected subcutaneously through a ⅝ inch 20 gauge needle into eitherthe upper right or left abdominal quadrant of about 90 patients. Bloodsamples were collected and analyzed for serum testosterone and LH over a112 day period, followed by another injection of the same amount andmonitoring for an additional 112 day period. Serum testosterone levelsdropped below the chemical castration level of 50 ng/mL after about day20, and maintained at that level throughout the 224 day study period.Only three patients experienced transient “breakthrough” events whereserum testosterone levels rose above 50 ng/mL, all of whom hadsuppression after the second injection at 112 days.

Example 5 Preparation of a 6-Month Leuprolide Acetate Controlled ReleaseFormulation

A polymer of the invention, comprising PLG copolymer segments and ahexanediol core, 85/15 L/G, with an inherent viscosity of 0.27, wasdissolved in N-methylpyrrolidone at a 50 wt % concentration, andradiation-sterilized. Approximately 550 mg of the irradiated polymersolution was transferred to a 1.25 mL female B-Braun syringe. In a 1 mLsterile male syringe, a sterile aqueous solution (0.5 mL) containing146.8 mg/ml leuprolide acetate was placed and lyophilized to dryness.Immediately prior to injection, the two syringes were coupled and thecontents mixed by making approximately 50 reciprocating transfersbetween the two syringes.

Example 6 Pre-Clinical Study of the 6-Month Formulation

Approximately 500 mg of the formulation of Example 5 containing about 60mg leuprolide acetate was injected per male beagle with a total of 6animals in the test group. Serum samples were collected and analyzed forserum testosterone starting prior to injection and continuing regularlythrough a 211 day time period.

For all 6 beagles, within about 14 days serum testosterone levels haddropped below 0.5 ng/mL, defined as the chemical castration level inhumans. Serum testosterone was maintained at this level, with no furtherinjections of the formulation, in excess of 190 days.

Example 7 Clinical Study of the 6-Month Formulation

The 85/15 L/G copolymer described in Example 5 was dissolved inN-methyl-2 pyrrolidone and loaded into 1.2 mL female syringes forsterilization by gamma-irradiation. In a sterile 1 mL male syringe, asterile-filtered solution of leuprolide acetate was placed andlyophilized to dryness. At the time of use, the two syringes werecoupled together and the contents mixed by making approximately 50reciprocating transfers between the two syringes. The product comprising45 mg of leuprolide per 0.375 mL of flowable composition was theninjected subcutaneously at baseline and at 168 days with a ⅝ inch, 19gauge hypodermic needle into the upper right or upper left abdominalquadrant of about 111 patients being treated for prostate cancer. Bloodsamples were collected and analyzed for testosterone and leutinizinghormone (LH). By day 28, 99% of the treatable patients had achievedtestosterone suppression. At study completion, 99% of the treatablepatients were below medical castrate testosterone levels of 50 ng/dlwith 88% at less than 20 ng/dl.

The invention has been described with reference to various specific andpreferred embodiments and techniques. However, it should be understoodthat many variations and modifications may be made while remainingwithin the spirit and scope of the invention.

1. (canceled)
 2. A polymer of Formula (I/II):

wherein: wherein L/G signifies a PLG copolymer segment, the H atoms atboth distal ends signify the hydrogen atoms borne by the terminalhydroxyl groups, and R^(a) is an alkylene diradical; R^(b) and R^(c) areeither hydrogen or methyl; the polymer is substantially insoluble inwater and body fluid, the polymer has substantially no titratablecarboxylic acid groups, the polymer has a weight average molecularweight from about 10 kD to about 50 kD, and the polymer in neat form isa solid at ambient temperature.
 3. The polymer of claim 2 wherein L/Gcomprises a lactide/glycolide copolymer segment with a lactide/glycolideratio of about 45/55 to about 99/1.
 4. The polymer of claim 2 whereinL/G comprises a lactide/glycolide copolymer segment with alactide/glycolide ratio of about 70/30 to about 90/10.
 5. The polymer ofclaim 2 having a weight average molecular weight of about 8 kD to about100 kD.
 6. The polymer of claim 5 having a weight average molecularweight of about 10 kD to about 50 kD.
 7. The polymer of claim 5 having aweight average molecular weight of about 15 kD to about 45 kD.
 8. Thepolymer of claim 5 wherein R^(a) is a linear unsubstituted carbon chain.9. The polymer of claim 8 wherein R^(a) is a linear unsubstituted carbonchain of 6 carbon atoms.
 10. The polymer of claim 5 wherein apolydispersity of the polymer is about 1.2 to about 2.0.
 11. The polymerof claim 5 wherein a polydispersity of the polymer is about 1.4 to about1.7.
 12. The polymer of claim 5 wherein an inherent viscosity of thepolymer is about 0.20 dL/gm to about 0.60 dL/gm.
 13. The polymer ofclaim 5 wherein an inherent viscosity of the polymer is about 0.25 dL/gmto about 0.40 dL/gm.